tbuckley/cabot-search huggingface dataset:
Abstract 967: Real-world transcriptomic biomarkers as replacement for immunohistochemistry and FISH studies in breast cancer
Authors: Maher Albitar, Andre Goy, Andrew Pecora, Deena Graham, Donna Donna McNamara, Ahmad Ahmad Charifa, Andrew IP, Wanlong Ma, Stanley Waintraub
Journal: Cancer Research (2023)

Abstract Background: Human epidermal growth factor receptor-2 (HER2) and hormone receptors are typically used as binary biomarkers for selecting breast cancer therapy. There is a need to explore the clinical relevance of these biomarkers as continuous variables. This is particularly relevant for the new class of antibody-drug conjugates (ADC), in which a relatively low HER2 expression level is adequate for targeting tumor cells. We explored the potential of RNA profiling, determined by next generation sequencing (NGS), to provide more flexible clinical biomarkers as compared with immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). Methods: Clinical and laboratory data from 57 breast cancers collected by the COTA real-world data company were used to study biomarker levels as detected by routine clinical transcriptomic tests. HER2 (ERBB2), estrogen receptor alpha (ESR1), and androgen receptor (AR) mRNA levels were compared with reported HER2 and estrogen receptor (ER) IHC and FISH results. Results: RNA levels accurately reflected and predicted HER2 amplification (see table below). Importantly, RNA data showed significant variation and overlap in the levels of ERBB2 mRNA between cases scored by IHC as zero, 1+, and 2+. This variation correlated with progression-free survival (PFS). Similarly, the ESR1 RNA levels accurately reflected ER status and demonstrated significant variation between positive cases. RNA data also showed significant variations in the AR levels. Patients wssith high AR mRNA levels had significantly better PFS (P=0.05). Patients expressing high ER and AR levels had significantly better PFS than those expressing low ESR1 and AR levels (P=0.03). Conclusions: These findings suggest that RNA analysis using NGS is an alternative to IHC and FISH. RNA provides continuous data that can determine cut-off points predicting response to therapy and should be explored in predicting ADC response. ERBB2 mRNA levels (FPKM) in various HER2 IHC groupss IHC Score Valid N Mean Median Minimum Maximum Quartile Range Std.Dev. Zero 19 231 243 63 537 170 110 Zero vs one 3 151 155 45 253 208 104 Zero to one vs one 18 397 302 172 845 365 222 One Vs two 13 495 423 159 1094 273 284 Two vs three 4 7523 7649 937 13859 7183 5310 Citation Format: Maher Albitar, Andre Goy, Andrew Pecora, Deena Graham, Donna Donna McNamara, Ahmad Ahmad Charifa, Andrew IP, Wanlong Ma, Stanley Waintraub. Real-world transcriptomic biomarkers as replacement for immunohistochemistry and FISH studies in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 967.
Abstract 4036: NMS-0963 is a novel potent, selective and orally available Syk inhibitor with promising preclinical activity in diffuse large B-cell lymphoma
Authors: Grazia Saturno, Michele Modugno, Paolo Orsini, Giovanni Cervi, Laura Buffa, Ilaria Motto, Nilla Avanzi, Marisa Montemartini, Fabio Gasparri, Gemma Texido, Arturo Galvani, Antonella Isacchi
Journal: Cancer Research (2023)

Abstract The B-cell receptor (BCR) is a key survival molecule for normal B cells and for most B-cell malignancies, such as Chronic Lymphocytic Leukaemia (CLL) and Non-Hodgkin’s Lymphomas (NHL) including Diffuse Large B-cell Lymphomas (DLBCL). Small molecule inhibitors of key signaling kinases involved in the BCR pathway, such as the Btk inhibitor ibrutinib and the PI3Kdelta inhibitor idelalisib, have already demonstrated significant clinical activity. Spleen tyrosine kinase (Syk) is a non-receptor cytoplasmic tyrosine kinase that plays a fundamental role in BCR signaling initiation thus representing an additional potential therapeutic target for the inhibition of the BCR pathway. Here, we report the discovery and characterization of NMS-0963, a novel potent, selective and orally available Syk inhibitor, identified through an integrated medicinal chemistry and rational design approach. NMS-0963 showed potent inhibitory effect on Syk in an in vitro biochemical assay and displayed a good selectivity profile on a broad panel of kinases. On-target potency was confirmed in a cell-based assay using BaF3 cells engineered to express constitutively activated Syk, showing potent inhibition of Syk activity resulting in antiproliferative effect with IC50s in the low nanomolar range. Effective inhibition of BCR-mediated signaling pathway was observed in DLBCL-derived cell lines. NMS-0963 showed favourable ADME profile and good in vivo pharmacokinetic profiles after oral administration in mouse, rat and dog. Furthermore, NMS-963 demonstrated striking in vivo efficacy in tumor models of CD79/Myd88 mutated DLBCL, superior to competitors. Together with a permissive preclinical safety profile, these results support a rational for clinical development of NMS-0963 in DLBCL. Citation Format: Grazia Saturno, Michele Modugno, Paolo Orsini, Giovanni Cervi, Laura Buffa, Ilaria Motto, Nilla Avanzi, Marisa Montemartini, Fabio Gasparri, Gemma Texido, Arturo Galvani, Antonella Isacchi. NMS-0963 is a novel potent, selective and orally available Syk inhibitor with promising preclinical activity in diffuse large B-cell lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4036.
Abstract 2764: Application of NanoBRET target engagement cellular assay for development of inhibitors against protein kinases, RAS, and epigenetic proteins in cancer therapy
Authors: Jianghong Wu, Yuan Wang, Shawn McGinley, Peter Gallagher, Li Liang, Alisha Di Lanni, Ashley Miles, Mohammad Haque, Yong Wan, Haiching Ma
Journal: Cancer Research (2023)

Abstract NanoBRET target engagement (TE) is the first biophysical technique that broadly enables the quantitative determination of protein inhibitor occupancy in live cells, without disruption of cellular membrane integrity. This quantitative capability is achieved in live cells via BRET with an optimized set of cell-permeable tracers, allowing the measurement of compound binding to a selected cellular target protein. Our NanoBret assay is scaled to 384-well plate format and Z’ analysis demonstrated the assay to be High Throughput Screening compatible. Protein kinases, RAS, and epigenetic proteins are very important drug targets. NanoBRET TE cellular assay has enabled the development of live-cell quantitative compound binding assays for &amp;gt;360 individual wild type and mutant protein kinases including serine/threonine-specific kinases, receptor tyrosine kinases, and all 20 cyclin-dependent kinases (CDKs). RAS is a well-known oncogene that is frequently mutated in most lung, pancreatic and colorectal cancers and is associated with poor disease prognosis. The recent discovery of a unique switch II binding pocket and successful inhibition of the KRAS (G12C) mutant by covalent inhibitors have led to the resurgence of interest in the design of inhibitors targeting RAS directly. Our data demonstrate that NanoBRET TE cellular assay can measure the apparent affinity of RAS inhibitors by competitive displacement of a NanoBRET RAS switch I/II pocket tracer, reversibly bound to the LgBiT- and SmBiT- KRAS, KRAS (G12C), KRAS (G12D), KRAS (G12V), KRAS (G13D), KRAS (Q61H), KRAS (Q61L), KRAS (Q61R), KRAS-G12A, KRAS-G12S, HRAS, HRAS-G12C, and HRAS-G12V fusion constructs co-transfected in live HEK293 cells. Our data also show NanoBRET cellular assay can be used to measure compound binding affinity to epigenetic drug target proteins such as BRD4, BRD4-BD1, BRD4-BD2, HDAC6, HDAC1, HDAC2, and HDAC3. Taken together, our results suggest NanoBRET TE cellular assay can serve as a great tool to facilitate new drug discovery against human cancers. Citation Format: Jianghong Wu, Yuan Wang, Shawn McGinley, Peter Gallagher, Li Liang, Alisha Di Lanni, Ashley Miles, Mohammad Haque, Yong Wan, Haiching Ma. Application of NanoBRET target engagement cellular assay for development of inhibitors against protein kinases, RAS, and epigenetic proteins in cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2764.
Abstract 6494: Postdiagnosis adherence to American Cancer Society cancer prevention guidelines and mortality among survivors of obesity-related cancers
Authors: Ying Wang, Christina Newton, Marjorie L. McCullough, Lauren R. Teras, Erika Rees-Punia, Caroline Um, Alpa V. Patel
Journal: Cancer Research (2023)

Abstract Purpose: To examine the combined and individual associations of postdiagnosis body mass index (BMI), physical activity, diet quality and alcohol consumption with all-cause mortality, cardiovascular disease mortality (CVDM) and cancer-specific mortality (CSM) among survivors of obesity-related cancers. Methods: American Cancer Society (ACS) Cancer Prevention Study-II Nutrition Cohort participants diagnosed with one of 13 invasive (but non-metastatic) obesity-related cancers between 1992 and 2003 were followed for mortality until 2018. Postdiagnosis lifestyle exposures were assessed at least one year after cancer diagnosis between 1999 and 2003. A lifestyle score ranging 0-8 was created according to ﻿adherence to the American Cancer Society (ACS) 2020 cancer prevention guidelines on BMI, physical activity, diet, and alcohol, with a score of 8 representing optimal behaviors for cancer prevention. Associations of the overall and individual component scores with mortality were estimated using multivariable-adjusted Cox proportional hazards regression models. Results: Among 7,945 cancer survivors, 4,862 died between 1992 and 2018. Higher ACS guideline score was associated with 6-8% lower risk of mortality per 1 point score increase (all-cause: HR: 0.94, 95% CI: 0.92-0.95; CVDM: HR:0.92, 95% CI:0.89-0.95; CSM: HR: 0.93, 95% CI 0.90-0.97) among cancer survivors. Individual scores of BMI, physical activity, and diet were inversely associated with overall mortality; however, alcohol score was positively associated with all-cause mortality, only among female survivors. Compared with participants who had low scores both before and after cancer diagnosis, those with high scores after diagnosis had lower risk of all-cause mortality, CVDM, and possibly CSM. Conclusion: Following ACS guidelines on diet and physical activity for cancer prevention after a cancer diagnosis is associated with better survival outcomes among survivors of obesity-related cancers. Citation Format: Ying Wang, Christina Newton, Marjorie L. McCullough, Lauren R. Teras, Erika Rees-Punia, Caroline Um, Alpa V. Patel. Postdiagnosis adherence to American Cancer Society cancer prevention guidelines and mortality among survivors of obesity-related cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6494.
Abstract 3754: The cell- and non-cell autonomous actions of UCA1 dysregulation in hypopharyngeal cancer
Authors: Li-Wha Wu
Journal: Cancer Research (2023)

Abstract Long non-coding RNAs (lncRNAs), encoding noncoding transcripts greater than 200 nucleotides, are multifunctional regulator of gene expression and play vital roles in various biological processes. Urothelial cancer-associated 1 (UCA1) is one such molecule and found to be dysregulated in the development of several cancer types, including those in bladder, colon, stomach, lung and breast. One previous study showed that an upregulation of UCA1 expression profile in hypopharyngeal cancer tissues relative to their adjacent normal counterparts significantly negated overall survival among these cancer patients. However, the molecular mechanism whereby UCA1 played any role in HPC, a subtype of head and neck cancer and often detected in advanced stages, remains elusive. In this report, we showed that ectopic UCA1 expression promoted cell migration and invasion while reducing cell proliferation. The increase of migration and invasion was accompanied by partial epithelial mesenchymal transition. By contrast, UCA1 depletion had the opposite effect. In addition to the presence of UCA1 in the culture medium (CM) and a stimulatory effect of CM derived from UCA1-OE cells on cell migration and invasion, we found a predominant nuclear localization of UCA1 in HPC cells. PTBP3, a RNA-binding protein, was identified as a novel interacting partner of UCA1 by RNA pulldown and mass spectrometry. PTBP3 silencing significantly reduced UCA1 mRNA expression, suggesting a regulatory role in UCA1 stability. While mapping the interacting domains between UCA1 and PTBP3, we are also in the process of identifying the involvement of UCA1-PTBP3 axis in hypopharyngeal carcinogenesis. We hope to validate if UCA1 can serve as a novel therapeutic target against or diagnostic marker for hypopharyngeal cancer. Citation Format: Li-Wha Wu. The cell- and non-cell autonomous actions of UCA1 dysregulation in hypopharyngeal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3754.
Abstract 4940: Proteasome and survivin inhibitors synergize to inhibit the growth of oral cancer organoids
Authors: Muhammad Furqan, Iffat Aleem, Muhammad Tahseen, Raza Hussain, Asif Loya, Muhammad Tariq Mahmood, Philippe Gautier, Kevin Myant, Saira Saleem, Amir Faisal
Journal: Cancer Research (2023)

Abstract Oral squamous cell carcinoma (OSCC) is the most prevalent subtype of head and neck cancers that has a disproportionately high incidence and mortality in developing countries in South-Central Asia, including Pakistan. The standard treatment for OSCC generally consists of surgery combined with radiotherapy or chemotherapy; however, the overall survival rates have not improved, and only ~50% of patients survive the disease. Therefore, identifying and validating new drug targets can provide new therapeutic options for improved treatment and better prognosis for OSCC patients. The present study aimed to develop an organoid model from patient-isolated primary tumour cells and determine their drug sensitivity profile coupled with mutational analysis. New combinations of targeted drugs with synergistic activity in oral cancer cells were identified through high-throughput screening followed by validation of their activity in oral cancer cells in 2D monolayer and 3D organoid cultures. Results indicate a synergistic activity of proteasome (PR-171) and survivin (YM155) inhibitors in all tested patient-derived tumour cells and four oral cancer cell lines. Moreover, chitosan-based nanocapsules harboring these drugs showed therapeutic efficacy comparable to free drug combinations, indicating a potential for efficient and targeted delivery. Next-generation sequencing data identified missense mutations in eleven cancer-related genes that encode BRAF, EGFR, KRAS, NRAS, HRAS, MEK1, PIK3CA, PTEN, NOTCH1, TP53 and TERT. The ongoing research aims to correlate the drug sensitivity data with the mutational profile of patient-derived tumour cells to find novel targets. In conclusion, we have developed 3D organoids from patient-derived primary tumours and utilized them to validate the synergistic combination between screen-identified proteasome and survivin inhibitors. Our preclinical study provides a rationale for further evaluation of the novel drug combination in vivo and in clinical settings. Citation Format: Muhammad Furqan, Iffat Aleem, Muhammad Tahseen, Raza Hussain, Asif Loya, Muhammad Tariq Mahmood, Philippe Gautier, Kevin Myant, Saira Saleem, Amir Faisal. Proteasome and survivin inhibitors synergize to inhibit the growth of oral cancer organoids. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4940.
Abstract 5050: Case report: A 17-year-old patient developed glioblastoma secondary to intracranial germ cell tumor and was stabilized with chemoradiotherapy combined with Tumor Treating Fields
Authors: Shaoqun Li, Mingyao Lai, Hainan Li, Juan Li, Jiangfen Zhou, Qingjun Hu, Minting Ye, Ruyu Ai, Junqiao Zhu, Lijun Huang, Linbo Cai
Journal: Cancer Research (2023)

Abstract Background: Germ Cell Tumor (GCT) is a rare intracranial tumor occurring in children and young adults. Some patients with GCT are curable with radiotherapy and chemotherapy. Due to long-term survival, the tumor secondary to radiotherapy is of concern. The treatment of the secondary tumor is less elaborated and worth exploring. Case Presentation: Here we report a patient with GCT who developed radiotherapy-induced glioblastoma. He was diagnosed as pineal gland GCT at the age of 12. Afterwards, he underwent a set of treatments, including chemotherapy, radiotherapy, and surgery. Unfortunately, after 5 years of tumor-free survival, he developed an intracranial mass involved the right thalamus and brainstem, around pineal region. The GCT recurrence was firstly considered, however, the failure of 7 cycles of chemotherapy drew attention. Then brain biopsy underwent by ROSA robot showed high-grade glioma. Next Generation Sequencing showed IDH-wildtype, MGMT methylation, CDKN2A/B homozygous deletion, EGFR amplification, the +7/−10 signature, which supported the diagnosis of glioblastoma. Resection operation is not applicable for this patient as the involvement of thalamus and brainstem. Considering the difficulty of treatment and poor prognosis of glioblastoma, re-radiotherapy is a feasible choice. Chemoradiotherapy with Tumor Treating Fields (TTFields) is a innovative try for secondary glioblastoma in a 17-year-old patient. After the combination therapy, the intracranial mass went regression and the patient has lived for more than 1 years. Conclusions: For the patients with brain tumor who anticipate long-term survival, the secondary tumor after radiotherapy is of concern. Secondary Glioblastoma is rare and difficult to treat. Chemoradiotherapy with TTFields is a feasible and safe treatment option for some patients, but we need more evidence to support. Citation Format: Shaoqun Li, Mingyao Lai, Hainan Li, Juan Li, Jiangfen Zhou, Qingjun Hu, Minting Ye, Ruyu Ai, Junqiao Zhu, Lijun Huang, Linbo Cai. Case report: A 17-year-old patient developed glioblastoma secondary to intracranial germ cell tumor and was stabilized with chemoradiotherapy combined with Tumor Treating Fields. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5050.
Abstract 4112: Evaluating the survival outcomes of an anti-isoaspELAVL4 response in a small cell lung cancer mouse model
Authors: Diego A. Velarde, Sarah A. Elmalh, Hannah Lee, Joseph Valdes, Matthew Gladstone, Ryan E. Dinigle, Martin Kast, Ite A. Offringa
Journal: Cancer Research (2023)

Abstract Small cell lung cancer (SCLC) has a 95% mortality rate and a 5-year survival of 8%, resulting in the death of over 20,000 Americans each year. There has been marginal improvement in therapy over the past 30 years, with the recent addition of immune checkpoint inhibition therapy modestly increasing overall SCLC patient survival from 10.3 to 12.3 months [PMID 30280641]. This highlights the need for additional SCLC therapies. Previous studies have identified a subset of SCLC patients (10-20%) exhibiting a naturally occurring immune response called ‘anti-HuD’. It is associated with improved response to therapy and improved survival [PMID 9256130; 26606748]. Previous work identified the anti-HuD antigen to be ELAVL4. The Offringa lab and collaborators determined that the antigenic epitope consists of isoaspartylated ELAVL4 (isoAspELAVL4) [PMID 27725125]; the protein carries isoaspartylated residues in the N-terminal region (amino acids 1-36). All tested Anti-Hu-positive SCLC patient serum samples reacted with isoAspELAVL4, and all examined SCLC tissue samples stained positive for isoAspELAVL4 [PMID 27725125]. Here we used the Trp53fl/fl; Rb1fl/fl inducible SCLC mouse model [PMID 14522252] to examine 1) whether immunization with isoAspELAVL4 prior to SCLC induction is protective, and 2) whether immunization with isoAspELAVL4 following completion of 3 rounds of cisplatin+etoposide therapy increases survival. In both cases, mice were immunized with recombinant N-terminal fragment of ELAVL4 (amino acids 1-117) generated in Clear Coli and emulsified in incomplete Freund’s adjuvant (IFA) or control (phosphate-buffered saline in IFA). The trajectories of mice have been monitored with a detailed body metric score and blood has been drawn every 2 weeks to monitor the anti-ELAVL4 antibody response. Kaplan-Meier analysis will be used to assess survival differences between the immunized and control groups and will be presented. The study will provide insight into interplay between SCLC and the immune response to isoAspELAVL4. Citation Format: Diego A. Velarde, Sarah A. Elmalh, Hannah Lee, Joseph Valdes, Matthew Gladstone, Ryan E. Dinigle, Martin Kast, Ite A. Offringa. Evaluating the survival outcomes of an anti-isoaspELAVL4 response in a small cell lung cancer mouse model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4112.